Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling
Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling
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DOI：
10.1016/j.bbrc.2008.01.061
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发表时间：
2008-03-28
影响因子：
3.1
通讯作者：
Miyake, Kensuke
中科院分区：
文献类型：
--
作者：
Tanimura, Natsuko;Saitoh, Shinichiroh;Miyake, Kensuke
Toll样受体4（TLR 4）激活两种不同的信号通路，分别诱导促炎细胞因子或I型干扰素（IFN）的产生。MyD 88和TIRAP/Mal是前一种途径必需的衔接分子，但不是后一种途径必需的衔接分子。相比之下，TRIF/TICAM-1和TRAM/TICAM-2对两者都是必不可少的。TIRAP是一种将MyD 88募集至质膜中活化的TLR 4的分选衔接子分子。TRAM被认为是TLR 4和TRIF之间的物理关联的桥梁。然而，很少有人知道TRAM如何在LPS反应期间与TLR 4或TRIF相互作用。在这里，我们表明，TRAM招聘TRIF的质膜。此外，LPS诱导上调TLR 4与TRAM的缔合以及它们随后易位到内体/溶酶体中。由TLR 4和TRAM组成的内化信号复合物与TRAF 3（TRIF下游的信号分子）共定位于内体/溶酶体中。这些结果表明TLR 4在从细胞表面重新定位后激活内体/溶酶体中的TRIF信号传导。(C)2008年爱思唯尔公司All rights reserved.
Toll-like receptor 4 (TLR4) activates two distinct signaling pathways inducing production of proinflammatory cytokines or type I interferons (IFNs), respectively. MyD88 and TIRAP/Mal are essential adaptor molecules for the former but not for the latter pathway. In contrast, TRIF/TICAM-1 and TRAM/TICAM-2 are essential for both. TIRAP is a sorting adaptor molecule recruiting MyD88 to activated TLR4 in the plasma membrane. TRAM is thought to bridge between TLR4 and TRIF by physical association. Little is known, however, how TRAM interacts with TLR4 or with TRIF during LPS response. Here, we show that TRAM recruits TRIF to the plasma membrane. Moreover, LPS induces upregulation of TLR4-association with TRAM and their subsequent translocation into endosome/lysosome. The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome. These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. (C) 2008 Elsevier Inc. All rights reserved.